Asthma is a respiratory disease which repeats stridor and attack due to airway contraction. The number of the asthma patients has been increasing constantly and is considered to further increase in the future.
Main morbid states of asthma are a) sudden contraction of smooth muscle which surrounds the airway and b) inflammatory reaction caused by the activation of infiltrative cells in respiratory organs including the lungs. Therefore, it is considered that inhibition of the airway smooth muscle contraction and inhibition or prevention of the activation of infiltrative celis are considered to be effective means for the treatment of symptoms of asthma.
For the treatment of asthma, xanthine derivatives such as aminophylline, theophylline and .beta.-stimulators such as procaterol are now mainly used as drugs which remit symptoms of asthma by dilating the bronchus. The action mechanism of these compounds is that they inhibit contraction of airway smooth muscle. through the increment of the concentration of cyclic adenosine 3',5'-monophosphate (cAMP) in the cells of the airway smooth muscle, which is effected by the activation of adenylate cyclase as a cAMP producing enzyme or by the inhibition of phosphodiesterase (PDE) as a cAMP hydrolyzing enzyme [Thorax, 46, 512-523 (991)].
However, xanthine derivatives generate systemic side effects such as decrease in blood pressure, cardiotonic action and the like [J. Cyclic Nucleotide and Protein Phosphorylation Res., 10, 551-564 (1985)] and, therefore, it is necessary to monitor its concentration in blood in order to prevent these systemic side effects. In addition, xanthine derivatives do not exert clear effect against asthma when it involves infiltration of inflammatory cells.
On the other hand, it is known that .beta.-stimulators generate side effects such as finger tremor, palpitation and the like, when the dose is increased because of their aptness to generate desensitization.
Studies conducted thereafter have revealed that the DPE, an enzyme which hydrolyses cAMP, is divided into at least four different types of I to IV having different distributions and functions [Pharmacological Therapy, 51, 13-33 (1991)]. Particularly, the type IV PDE hydrolyses cAMP in a specific fashion without acting upon cyclic guanosine 3',5'-monophosphate (cGMP) among nucleotides, and its presence is found in both airway smooth muscle and infiltrative cells.
Incidentally, PDE V is known as an enzyme which degrades cGMP.
Concentration of cAMP in cells is set by the balance of the cAMP production rate by adenylate cyclase and the cAMP hydrolyzation rate by PDE. In consequence, intracellular cAMP concentration can be increased by stimulating adenylate cyclase or inhibiting PDE. Increase in the intracellular cAMP concentration induces inhibition of contraction of the airway smooth muscle and inhibition of the activation of inflammatory cells [Clin. Exp. Allergy, 22, 337-344 (1992), Drugs of the Future, 17, 799-807 (1992)].
Also, it has been reported that a type IV PDE inhibitor shows an action to inhibit eosinophiles infiltration by antigen and platelet activating factor in guinea pigs [Eur. J. Pharmacol., 255, 253-256 (1994)] and inhibits release of cytotoxic proteins (MBP, ECP) from eosinophiles [Br. J. Pharmacol., 115, 39-47 (1995)]. It has been reported also that it shows an action to inhibit contraction of the airway smooth muscle caused by contractile substances (histamine, LTD.sub.4, methacholine) [Br. T. Pharmacol., 113, 1423-1431 (1994)], inhibits production of IL-4 which is a member of cytokine which is considered to be concerned deeply in asthma [J. Invest. Dermatol., 100, 681-684 (1993)], expresses an action to inhibit acceleration of vascular permeability in the airway [Fundam. Clin. Pharmacol., 6, 247-249 (1992)] and shows an action to inhibit airway hyperreactivity [Eur. J. Pharmacol., 275, 75-82 (1995)].
In consequence, an agent having excellent activity to inhibit type IV PDE is expected as an anti-asthma drug which hardly generates side effects and can remit or prevent asthmatic symptoms effectively.
It is known that a compound having a quinazolin-2-one structure has PDE inhibiting activity which is not limited to the type IV (cf. International Patent Publication 94/12499), but its structure is different from that of the pyrido[2,3-d]pyrimidine compound provided by the present invention.
On the other hand, a compound having a 4-phenylpyrido[2,3-d]pyrimidin-2-one structure has been reported by G. E. Hardtmann et al. in U.S. Pat. No. 3,758,475. In this patent, a compound having anti-inflammatory activity, which can be recognized by a carrageenin-induced edema suppression test, is shown by the following general formula: ##STR3## wherein R is hydrogen or lower alkyl of 1 to 5 carbon atoms, e.g., methyl;
R' is lower alkyl of 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, t-butyl, etc.; allyl; methallyl; propargyl; or cycloalkyl of 3 to 6 carbon atoms, e.g., cyclopropyl; and PA1 R" is phenyl or substituted phenyl of the formula: ##STR4## and Y represents halo of atomic weight of from 19 to 80; lower alkyl of 1 to 4 carbon atoms; or lower alkoxy of 1 to 4 carbon atoms; and PA1 Y' represents hydrogen, halo, lower alkyl or lower alkoxy (all as defined for Y). PA1 R.sup.1 : a lower alkyl group, a cycloalkyl-lower alkyl group or a cycloalkyl group, PA1 R.sup.2 : a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower alkanoylthio-lower alkyl group, a lower alkanoyl-lower alkyl group, a hydroxyimino-lower alkyl group, a lower alkoxyimino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, PA1 R.sup.3 : a hydrogen atom, a halogen atom or a lower alkyl group, PA1 R.sup.4 : a hydrogen atom or a lower alkyl group, PA1 R.sup.5 : a cycloalkyl group which may be substituted with the same group of R.sup.6 ; a naphthyl group which may be substituted with the same group of R.sup.6 ; a five- or six-membered monocyclic hetero ring group having 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be substituted with the same group of R.sup.6 and which may be condensed with benzene ring; or a group represented bythe formula ##STR6## and R.sup.6 : a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxyl group, a lower alkoxy group, a cyano group or a nitro group, with the proviso that R.sup.2 is a group other than hydrogen atom when R.sup.5 is a group represented by the formula ##STR7## R.sup.6 is a halogen atom, a lower alkyl group or a lower alkoxy group, R.sup.1 is a lower alkyl group or a cycloalkyl group, R.sup.3 and R.sup.4 are both a hydrogen atom and X is an oxygen atom.] PA1 with the proviso that R.sup.10 is a group other than a hydrogen atom and a lower alkyl group when R.sup.5 is a group represented by the formula ##STR11## R.sup.6 is a halogen atom, a lower alkyl group or a lower alkoxy group, R.sup.1 is a lower alkyl group or a cycloalkyl group, R.sup.3 and R.sup.4 are both a hydrogen atom and X is an oxygen atom.] PA1 R.sup.2 : the same group of R.sup.2, which may be protected, PA1 R.sup.3 : the same group of R.sup.3, excluding halogen atoms, PA1 Y.sup.2, Y.sup.3 and Y.sup.4 : the same or different from one another, and each represents a halogen atom, PA1 Z.sup.2 and Z.sup.3 : leaving groups advantageous for the pyridine synthesis reaction, and PA1 Ts: a p-toluenesulfonyl group.) PA1 iii) Halogenation of ring PA1 Respiratory diseases [e.g., bronchial asthma (including atopic asthma), chronic bronchitis, pneumonia, adult respiratory distress syndrome (ARDS) and the like], PA1 inflammatory diseases [e.g., atopic dermatitis, conjunctivitis, urticaria, acquired immunodeficiency syndrome (AIDS), keloid formation, rhinitis, iridocylitis, gingivitis, periodontitis, alveolar pyorrhea, gastritis, ulcerative colitis, Crohn disease, gastrointestinal ulcer, esophagitis, myositis, encephalitis (myasthenia gravis, multiple sclerosis and neuritis), hepatitis, cicatrization, nephritis (including proliferative nephritis), peritonitis, pleuritis, scleritis, scleroderma, burn injury and the like], PA1 a systemic or local arthropathy (e.g., osteoarthrosis, gouty arthritis, chronic rheumatoid arthritis, malignant rheumatoid, psoriatic arthritis and the like), PA1 proliferative diseases [e.g., malignant tumor, leukemia, proliferative dermatopathy (keratosis and various types of dermatitis), collagen disease and the like], PA1 diseases related to nervous function abnormality (e.g., learning, memory and cognition disturbances related to nervous degeneration diseases such as Alzheimer disease, Parkinson disease and the like, multiple lateral sclerosis, senile dementia, amyotrophic lateral sclerosis, acute demyelinating neuritis, muscular dystrophy and the like), PA1 diseases with mental function abnormality (e.g., manic-depressive psychosis, schizoid, anxiety, panic and the like), PA1 inflammation due to organ transplantation and the like (e.g., reperfusion injury, graft versus host reaction and the like), PA1 diseases which require protection of nerves and cells [e.g., cardiac arrest, spinal cord injury, intermittent claudication, ischemic diseases (e.g., angina pectoris, myocardial infarction, stroke, head injury and the like) and the like], PA1 diseases related to micturition (e.g., diabetes insipidus, urethritis, urinary incontinence, cystitis, irritable bladder, neurogenic bladder, uremia, tubular disorder, pollakiuria, urinary retention and the like), PA1 endocrine diseases including diabetes mellitus (e.g., diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, amyloidosis, pancreatitis, thyroiditis, obesity, prostatic hypertrophy and the like), PA1 diseases in which tumor necrosis factor (TNF) and other cytokine (IL-1, IL-6 and the like) are concerned [e.g., psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn disease, sepsis, septic shock, endotoxin shock, Gram negative bacillus sepsis, toxic shock syndrome, nephritis, hepatitis, infection (bacterial and viral), circulatory failure (heart failure, arteriosclerosis, myocardial infarction, stroke) and the like], PA1 autoimmune diseases (e.g., systemic lupus erythematosus, atrophic gastritis, thyroid gland disease, glomerulonephritis, orchitis, adrenal disease, hemolytic anemia, oophoritis and the like), PA1 circulatory organ diseases (e.g., hypertension, angina pectoris, heart failure, myocarditis, epicarditis, endocarditis, valvulitis and the like), PA1 diseases of vascular and blood systems (e.g., angitis, aneurysm, vascular endothelial injury, thrombosis inflammation, granuloma, cerebrovascular inflammation, arteriosclerosis, perivascular inflammation, leukopenia, thrombocytopenia, sarcoidosis and the like), PA1 diseases in which immune allergy reactions are concerned (e.g., contact dermatitis, serum sickness, drug allergy, Goodpasture syndrome, lymphomatosis, rheumatic fever, AIDS, anaphylactic shock and the like), and PA1 other diseases [glaucoma, spastic paralysis, impotence, diseases with pain (e.g., contusion, headache and the like), cervico-omo-branchial syndrome, nephropathy, renal insufficiency, hepatic insufficiency and obesity]. PA1 respiratory diseases [e.g., bronchial asthma (including atopic asthma), chronic bronchitis, pneumonia, ARDS and the like], PA1 inflammatory diseases [e.g., atopic dermatitis, conjunctivitis, urticaria, AIDS, keloid formation, rhinitis, iridocylitis, gingivitis, periodontitis, alveolar pyorrhea, gastritis, ulcerative colitis, Crohn disease, gastrointestinal ulcer, esophagitis, myositis, encephalitis (myasthenia gravis, multiple sclerosis and neuritis), hepatitis, cicatrization, nephritis (including proliferative nephritis), peritonitis, pleuritis, scleritis, scleroderma, burn injury and the like], and PA1 diseases in which tumor necrosis factor (TNF) and other cytokine (IL-1, IL-6 and the like) are concerned [e.g., psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn disease, sepsis, septic shock, endotoxin shock, Gram negative bacillus sepsis, toxic shock syndrome, nephritis, hepatitis, infection (bacterial and viral), circulatory failure (heart failure, arteriosclerosis, myocardial infarction, stroke) and the like].
Similar anti-inflammatory compound has been reported also by G. E. Hardtmann et al. in J. Med. Chem. (Vol. 17, No. 16, 636-639, 1974).
Also, a method for the inhibition of platelet agglutination in which a 1-substituted-4-arylpyrido[2,3-d]pyrimidin-2-one, a compound similar to the aforementioned compound, is administered has been reported [cf. an unexamined published Japanese patent application (kokai) No. 53-94040].
Some of the compounds provided by the present invention are included in the general formula shown in the aforementioned U.S. Patent, because they correspond to the compound of the formula in which R is a lower alkyl group, R' is a lower alkyl group or a C.sub.3-6 cycloalkyl group and R" is a phenyl group having a halogen atom, a lower alkyl group or a lower alkoxy group on its meta position.
However, there are no illustrative descriptions in Examples and other parts of the U.S. Patent about a compound which has a halogen atom or a lower alkyl group only at the meta position of phenyl group and also has a lower alkyl group at the 7-position of pyrido[2,3-d]pyrimidine. In addition, the aforementioned U.S. Patent describes only about anti-inflammatory activity and does not describe or suggest about inhibitory action against the type IV PDE and anti-asthma action.